Assortative mixing as a source of bias in epidemiological studies of sexually transmitted infections: the case of smoking and human papillomavirus

Abstract

For studies examining risk factors of sexually transmitted infections (STIs), confounding can stem from the characteristics of the partners of study subjects, and persist after adjustment for the subjects' individual-level characteristics. Two conditions can produce confounding by the subjects' partners: C1) partner choice is assortative by the risk factor examined and, C2) sexual activity is associated with the risk factor. We term this bias the assortativity bias. The objective of this paper is to illustrate the potential impact of the assortativity bias in studies examining STI risk factors, using smoking and Human papillomavirus (HPV) as an example. We developed an HPV transmission-dynamic mathematical model in which we nested a crosssectional study assessing the smoking-HPV association. In our base-case, we assumed 1) no effect of smoking on HPV, and 2) conditions C1-2 hold for smoking (based on empirical data).The assortativity bias caused an overestimation of the odds ratio (OR) in the simulated study after perfect adjustment for the subjects' individual-level characteristics (adjusted OR=1.51 instead of 1.00). The bias was amplified by a lower basic reproductive number (R 0 ), greater mixing assortativity and greater sexual activity among smokers. To mitigate the assortativity bias studies should adjust for the characteristics of study partners. 2 Word count=200Infectious diseases are transmissible, which implies that the contact network of an individual is a crucial determinant of his risk of infection (1). Thus, an individual's risk of infection not only depends on individual-level risk factors, such as his age and gender, but on network-level risk factors. A classic example of this particularity of infectious diseases is herd immunity: vaccinating a portion of the population reduces the chance of non-vaccinated individuals being exposed to the infectious agent (2). Hence, an individual's risk of infection following the introduction of vaccination depends on his/her vaccine status (individual-level risk factor),

Evidence of synergistic relationships between HIV and Human Papillomavirus (HPV): systematic reviews and meta‐analyses of longitudinal studies of HPV acquisition and clearance by HIV status, and of HIV acquisition by HPV status

“…Recent modelling analyses of HPV and HIV, and of HSV‐2 and HIV, have suggested that observed associations could be explained by confounding by sexual risk factors, in the absence of biological interaction . However, these effects are likely to be greater for cross‐sectional studies whereas our review was based on longitudinal studies . Furthermore, we found some evidence in review 2 that adjustment for key confounding variables including sexual behaviour actually strengthened the associations.…”

“…Conversely, mathematical modelling to assess potential biases in STI and HIV interaction estimates for different study designs has suggested that whilst statistical adjustment can help reduce overestimation due to confounding, the magnitude of association could also be underestimated in the presence of misclassification of exposure . Although we only included longitudinal studies, which established the sequence of events for HPV and HIV infections, there is still some potential for misclassification bias of both HIV and HPV exposure status.…”

“…That said, even with adjusted estimates the presence of residual confounding cannot totally be excluded, especially by partner and/or partnership characteristics (influencing the likelihood of exposure to HPV and HIV) or previous HPV infections (which may protect or predispose to HPV infection) [71]. Conversely, mathematical modelling to assess potential biases in STI and HIV interaction estimates for different study designs has suggested that whilst statistical adjustment can help reduce overestimation due to confounding, the magnitude of association could also be underestimated in the presence of misclassification of exposure [78,79]. Although we only included longitudinal studies, which established the sequence of events for HPV and HIV infections, there is still some potential for misclassification bias of both HIV and HPV exposure status.…”

Recurring infection with ecologically distinct HPV types can explain high prevalence and diversity

“…3B). Unmeasured assortative mixing (44) and simultaneous exposure to multiple HPV types through sexual partnerships (45) can confound associations between HPV incidence and past exposures. Residual confounding may be a problem, because the initial infection risk is low and sensitive to host-specific risk factors.…”

Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis

“…The presence of HSV-2 infection (particularly incident HSV-2 infection) might be a marker of having had sex with a partner infected with HIV because of the higher prevalence of HSV-2 among HIV-infected than among non-HIV-infected individuals. 76 , 77 , 78 Except for serodiscordant-couple studies, in which partner HIV status was known, few studies controlled for partner characteristics. Additionally, some studies inappropriately adjusted for genital ulcer disease, which might have biased pooled estimates toward the null value because HSV-2 commonly causes genital ulcers and these act as a point of entry for HIV.…”